Glycopeptide and lipoglycopeptide antibiotics are a class of biologically produced or semi-synthetic antimicrobial agents which affect bacterial cell wall and/or membrane integrity (Williams et al., Angewandte Chemie International Edition in English 38:1172-1193 (1999); Nicolaou et al., Angewandte Chemie International Edition in English 38:2097-2152 (1999); Kahne et al., Chemical Reviews 105:425-448 (2005); Pace et al., Biochemical Pharmacology 71:968-980 (2006)). The best known glycopeptide and lipoglycopeptide antibiotics include vancomycin, teicoplanin, oritavancin (U.S. Pat. No. 5,840,684), dalbavancin (U.S. Pat. No. 5,750,509) and telavancin (U.S. Pat. No. 6,635,618). The first two drugs were proven clinically and microbiologically to have potent activity against gram-positive organisms and the latter three drugs are in clinical trials. Oritavancin, dalbavancin and telavancin possess extremely attractive pharmacological profiles with potent activity against gram-positive organisms, including methicillin-resistant Staphylococcus aureus, intermediate and fully vancomycin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus spp., and Streptococcus spp.
Oritavancin is a semi-synthetic lipoglycopeptide in clinical development against serious gram-positive infections. It exerts activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). The rapidity of its bactericidal activity against exponentially-growing S. aureus (≧3-log reduction within 15 minutes to 2 hours against MSSA, MRSA, and VRSA) is one feature that distinguishes it from the prototypic glycopeptide vancomycin (McKay et al., Time-kill kinetics of oritavancin and comparator agents against Staphylococcus aureus, Enterococcus faecalis and Enterococcus faecium. J Antimicrob Chemother. 2009 Apr. 15. (Epub ahead of print) PubMed PMID: 19369269).
Recent work demonstrated that oritavancin has multiple mechanisms of action that can contribute to cell death of exponentially-growing S. aureus, including inhibition of cell wall synthesis by both substrate-dependent and -independent mechanisms (Allen et al., FEMS Microbiol Rev 26:511-32 (2003); Arhin et al., Newly defined in vitro quality control ranges for oritavancin broth microdilution testing and impact of variation in testing parameters. Diagn Microbiol Infect Dis. 2008 Sep., 62(1):92-5.; Wang et al., Probing the mechanism of inhibition of bacterial peptidoglycan glycosyltransferases by glycopeptide analogs, 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Ill. (2007)), disruption of membrane potential and increasing membrane permeability (McKay et al., Oritavancin Disrupts Transmembrane Potential and Membrane Integrity Concomitantly with Cell Killing in Staphylococcus aureus and Vancomycin-Resistant Enterococci, 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Calif. (2006)), and inhibition of RNA synthesis (Arhin et al., Effect of Polysorbate-80 on Oritavancin Binding to Plastic Surfaces-Implications for Susceptibility Testing, 17th European Congress of Clinical Microbiology and Infectious Diseases, Munich, Germany (2007)). The ability of oritavancin but not vancomycin to interact with the cell membrane, leading to loss of membrane integrity and collapse of transmembrane potential, correlates with the rapidity of oritavancin bactericidal activity (McKay et al., Oritavancin Disrupts Transmembrane Potential and Membrane Integrity Concomitantly with Cell Killing in Staphylococcus aureus and Vancomycin-Resistant Enterococci, 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Calif. (2006)).